Syntheses of omarigliptin have previously been described in PCT international patent applications numbers WO 2010/056708 and WO2013/003250. The process described in WO 2010/056708 does not result in a favorable yield of the compound of structural Formula Ia, as it results in a racemic mixture. WO2013/003250 describes the following scheme to make the compound of structural Formula Ia, an intermediate for synthesizing omarigliptin:

In WO2013/003250, synthesis of the compound of structural Formula Ia involves using benzenesulfonic acid (BSA) to remove the Boc protecting group of the compound of structural Formula 1, by first forming a BSA salt of the compound of structural Formula 1a. The BSA salt is then isolated and undergoes reductive amination with Boc-ketone of the compound of structural Formula 7, to produce the compound of structural Formula Ia, as a 19:1 diastereomeric mixture. The BSA mediated Boc deprotection requires up to 72 h to reach full conversion.
An alternative process which eliminates the need to isolate the BSA salt of the compound of Formula 1a and reduces the overall reaction time of the process is desired. The inventors have now discovered a process for making the compound of structural Formula Ia which eliminates the step of isolating a salt of the compound of structural Formula 1a and reduces the overall reaction time. The present process also produces an end-of reaction homogeneous solution via reductive amination, which facilitates crystallization of the compound of structural Formula Ia. The described process also improves the diastereoselectivity, overall yield, cost and cycle time over the process described in WO2013/003250.
WO2013/003250 also describes the Boc deprotection of the compound of Formula Ia to produce omarigliptin (Formula I) shown below. As described in WO2013/003250, the Boc deprotection of the compound of Formula Ia involves aging the substrate in aqueous sulfuric acid in DMAc at 30° C. for 15-20 h, then working up with ammonium hydroxide. This work up produces large amounts of poorly soluble ammonium sulfate which co-crystallizes with the desired product. As a result, isolation of the desired product requires a long cycle time for filtration, washing and drying.

Because the processes described herein use trifluoroacetic acid with or without a co-solvent for the transformation of the compound of Formula Ia to omarigliptin, which offers good solubility for the compound of Formula Ia, omarigliptin is achieved with fast reaction kinetics and good purity profiles.